心肌梗塞和脑梗塞溶栓治疗的证据比较

心肌梗塞和脑梗塞溶栓治疗的证据比较

摘要：

关键词：

心肌梗塞和脑梗塞是对人们健康危害极大的一种疾病，死亡率高。它们都是由于血管被血栓阻塞引起的心、脑细胞供血不足所致的缺血性坏死。溶栓药物可以通过溶解血栓、恢复血供来减少心、脑细胞的损伤。溶栓治疗在心肌梗塞已经成为经典的治疗方法之一，大量的随机对照试验（randomized control trial, RCT）已证实，溶栓治疗能够降低死亡率。但心肌梗塞患者是否溶栓治疗是最佳选择？PTCA相对于溶栓治疗优势何在？由于相同的病理生理机制，脑梗塞患者溶栓治疗情况如何？是最佳选择吗？等等，都是临床医生关心的问题。本文通过复习近年来所发表的，能提供临床证据的RCT和系统评价，对上述问题进行阐述说明。一．检索资源和内容

我们检索了最新Cochrane图书馆（2001年第2期）、MEDLINE（1980－2001.6），收集有关心肌梗塞和脑梗塞溶栓治疗的系统评价和Meta分析以及大型的RCT。

二．研究结果

1．脑梗塞溶栓治疗已完成2个系统评价（systematic review，SR）。一个SR是评价溶栓治疗对脑梗塞的有效性和安全性，共纳入17个RCT，5216名患者，以死亡率、致残率为试验终点，15个RCT为双盲设计，溶栓药物包括尿激酶、链激酶、重组组织纤维蛋白溶酶原激活物（recombinant tissue plasminogen activator，tPA）或重组尿激酶原（recombinant pro-urokinase），2个试验采取动脉内给药，余均是静脉途径用药。一半的试验资料是静脉用tPA。

trials testing intravenous tissue Plasminogen Activator. Thrombolytic therapy significantly increased the odds of death within the first ten days (odds ratio [OR] 1.85, 95% confidence interval [CI] 1.48 to 2.32). The main cause of the increase in deaths was fatal intracranial haemorrhage following thrombolysis (OR 4.15, 95% CI 2.96 to 5.84). Symptomatic intracranial haemorrhage is also increased following thrombolysis (OR 3.53, 95% CI 2.79 to 4.45). Thrombolytic therapy also increased the odds of death at the end of follow-up (OR 1.31, 95% CI 1.13 to 1.52). Despite this, thrombolytic therapy, administered up to six hours after ischaemic stroke, significantly reduced the proportion of patients who were dead or dependent (modified Rankin 3 to 6) at the end of follow-up (OR 0.83, 95% CI 0.73 to 0.94). For patients treated within three hours of stroke, thrombolytic therapy appeared more effective in reducing death or dependency (OR 0.58, 95% CI 0.46 to 0.74) with less adverse effect on death (OR 1.11, 95% CI 0.84 to 1.47). There was heterogeneity between the trials that could have been due to : thrombolytic drug used, variation in the concomitant use of aspirin and heparin, severity of the stroke, and time to treatment. Trials testing intravenous recombinant tissue Plasminogen Activator suggest that it may be associated with slightly less hazard and more benefit when given up to six hours after stroke - death within the first ten days OR 1.24, 95% CI 0.85 to 1.81, death at the end of follow-up OR 1.16, 95% CI 0.94 to 1.44, dead or

dependent at the end of follow-up OR 0.79, 95% CI 0.68 to 0.92. One trial that tested thrombolysis plus aspirin showed an increase in deaths of patients given both drugs in combination compared with thrombolysis alone. Reviewers' conclusions: Thrombolytic therapy increases deaths within the first seven to ten days, and deaths at final follow-up. Thrombolytic therapy also significantly increases symptomatic and fatal intracranial haemorrhage. These risks

are offset by a reduction in disability in survivors, so that there is, overall, a significant net reduction in the proportion of patients dead or dependent in activities of daily living. The data from trials using intravenous recombinant tissue Plasminogen Activator, from which there is the most evidence on thrombolytic therapy so far, suggest that it may be associated with less hazard and more benefit. There was heterogeneity between the trials and the optimum criteria to identify the patients most likely to benefit and least likely to be harmed, the agent, dose, and route of administration, are not clear. The data are promising and may justify the use of thrombolytic therapy with intravenous recombinant tissue Plasminogen Activator in experienced centres in selected patients. However, the widespread use of thrombolytic therapy in routine clinical practice at this time cannot be supported. Further trials will be needed to identify which patients are most likely to benefit from treatment and the environment in which it may best be given, before thrombolytic therapy should be adopted on a

wider scale.

结果显示，溶栓治疗可以降低随访终点时的死亡率和残废率（OR=0.83，95%CI 0.73-0.94），相当于每治疗1000人可以减少44人的死亡或残废。r-tPA在6个试验共有2764人使用，结果显示r-tPA效果更好，（OR=0.79，95%CI 0.68-0.92），相当于每治疗1000人减少57人的死亡或残废。

1. 1短期的死亡率（10天内）

溶栓治疗增加短期的死亡率（OR=1.85，95%CI 1.48-2.32），等于说每治疗1000人增加了68人的短期死亡；

1. 2随访终点的死亡率

溶栓治疗增加了随访终点时的死亡率（OR=1.31，95%CI 1.13-1.52），等于每治疗1000人引起随访终点时的死亡增加了36人；如果使用r-tPA，死亡率增加不明显（OR=1.16，95%CI

0.94-1.44），相当于每治疗1000人随访终点时的死亡增加了18人。

1. 3致死性的颅内出血

致死性的颅内出血是引起死亡的主要原因，溶栓组中致死性颅内出血的发生率比对照组几乎高出5倍（OR=4.15，95%CI 2.96-5.84）；使用r-tPA比使用链激酶引起颅内出血的发生率低：每治疗1000人，r-tPA增加了29例致死性颅内出血（OR=3.2，95%CI 2.0-5.2）而链激酶则增加92例致死性颅内出血（OR=6.03，95%CI 3.47-10.47）。

1. 4非致死性但有临床症状的颅内出血

溶栓治疗会明显增加非致死性但有临床症状的颅内出血（OR=3.5，95%CI 2.8-4.5），相当于每治疗1000人增加了70人颅内出血。

另一SR是评价不同溶栓制剂、给药途径和剂量对脑梗塞的效果。纳入8个RCT，1334个病人，分配方案进行了隐藏，所有试验均在日本进行，adequate. All the trials were conducted in Japan. Different doses (of tissue plasminogen activator or urokinase) were compared in seven trials. Different agents (tissue plasminogen activator versus urokinase, or tissue-cultured urokinase versus conventional urokinase) were compared in three trials. Few data were available for functional outcomes. A higher dose of thrombolytic therapy was associated with a five-fold increase in fatal intracranial haemorrhages (odds ratio 5.02, 95% confidence interval 1.56 to 16.18). This was based on 11 events among 369 higher-dose patients and one event among 356 lower-dose patients in six trials. There was a non-significant trend towards more early deaths or clinically significant intracranial haemorrhages. No difference in late deaths or extra-cranial haemorrhages was shown between low and higher doses. However, very few of these events occurred. No difference was shown between the different thrombolytic agents tested. Reviewers'

conclusions: There is not enough evidence to conclude whether lower doses of thrombolytic agents might be safer or more effective than higher doses in acute ischaemic stroke. It is not possible to conclude whether one agent might be better than another, or which route of administration might be best. No comparative

心肌梗塞：到目前为止，仅完成1篇关于溶栓治疗与PTCA疗效比较的SR，但从MEDLINE 检索到相关的一些大型临床RCT。

2.1病死率

溶栓治疗可以降低病死率：GISSI（意大利治疗心肌梗死生存试验）证实SK使病死率减少20%-25%。ASSET（北欧早期溶栓治疗）证实t-PA降低病死率26%，AIMS（英国APSAC治疗心肌梗死研究）由于降低病死率约50%而提前终止试验。国际上最大的溶栓试验（ISIS-Ⅲ国际心肌梗死生存试验-Ⅲ）比较了SK，t-PA、APSAC疗效，5周病死率分别为10.5%、10.3%、10.6%，均使病死率明显降低。最近溶栓治疗试验汇总资料表明，溶栓组0-35天AMI病死率为9.4%显著低于对照组11.3%，但36-182天病死率（3.8%比4.0%）及>183天（8.3%比8.3%）却无明显差异。

2.2治疗时间窗：

从胸痛发作到溶栓的时间间隔，一般来讲越短越好，0～6小时入选的溶栓治疗可使病死率(8.7%)较对照组(11.1%)减少24%±3%；如果7～12小时入选（11.0%）较对照组（12.6%）减少15%±5%；13～24小时入选（10%）较对照组（10.5%）减少4%±7%。说明溶栓的时间延迟越长，效果越差。

LATE试验（1993年）证实了6-24小时晚期溶栓仍有益，该试验评价了急性心肌梗塞后6～24小时开始应用rt-PA的效果与安慰剂对照。rt-PA组和对照组35天死亡率分别为8.86%和10.31%，相对降低14.1%。但12小时内进行溶栓治疗的分析表明rt-PA组死亡率显著降低：两组35天死亡率分别为8.9%和11.97%，相对降低25.6%(95%CI为6.3% ～45.0%，P=0.023)。

2.3安全性：

t-PA 0-35天脑出血发生率为0.5%（134/24387），显著高于SK0.3%（64/24457），2P<0.00001。年龄越大，t-PA组脑出血发生率越高。APSAC组脑出血发生率为0.5%（76/13849）也显著高于SK0.2%（33/13858），2P<0.0001。

2.4溶栓药物的比较

GISSI-2，ISIS-3，ISSIS-2等试验提示：各种溶栓药物均明显降低死亡率，效果无明显差异。t-PA 与SK合用，与单独使用t-PA、SK并无明显差异。

2.5溶栓治疗与PTCA疗效比较

被评价的转归结局包括：研究终点时的总死亡率、再梗塞、任何形式的中风、死亡与再梗塞的复合终点、反复心肌缺血、严重出血和冠脉旁路手术。主要结果是：收集了10个临床试验，包括2573例病人。与溶栓治疗相比，直接PTCA疗效更好。短期死亡率显著降低（Relative reduction risk相对危险降低RRR=32%, 95%CI=5%-50%）。观察到再梗塞有同样降低（RRR=52%，95% CI=30%-67%），反复心肌缺血（RRR=54%，95%CI=39%-66%），死亡与再梗塞的复合终点（RRR=46%，95%CI=30-58%），中风明显降低66%（95% CI=28%-84%）。大出血的发生无显著差异（RR=1.18,95% CI=0.73-1.90，但这个可信区间较大）。考虑死亡及再梗塞作为联合终点，直接PTCA的优越性优于溶栓，但与加速性t-PA相比优越性较低(RR=0.70,95%CI=0.51-0.97)，与链激酶相比较高（RR=0.30,95%CI=0.17-0.53）。

三．讨论

在脑梗塞的治疗中，尽管溶栓治疗会增高10天内的死亡率以及随访终点时的死亡率，并增加了颅内出血的发生率，但总的说来，溶栓治疗是利大于弊，使幸存的患者病残率减少。在MAST-I试验中，研究了联合使用阿司匹林和溶栓治疗的安全性，结果提示联合使用阿司匹

林和链激酶会明显增高各阶段的脑血管性死亡（OR=2.0，95%CI 1.1-3.7）和致死性的颅内出血（OR=2.2，95%CI 1.0-5.0）。根据所得的资料，溶栓治疗引起的死亡主要是由于24小时内联合使用抗凝剂或抗血小板药物，并且接受溶栓治疗的病人病情重，脑梗塞面积较大。目前尚无充足的证据回答关于溶栓治疗的时间窗是多少，但是NINDS试验中，使用r-tPA在3小时内进行溶栓治疗可以降低随访期内病人的死亡率及病残率。由于病例数少，需要更大型的随机临床试验来证实。美国FDA及加拿大的溶栓治疗指南中指出：r-tPA治疗急性缺血性中风的时间窗为3小时内。关于溶栓治疗的不同药物和同一药物的不同剂量，仅有一篇系统评价进行了研究，结果是：8个试验共1334名病人。大剂量比小剂量要增加致死性的颅内出血5倍（OR=5.02，95%CI 1.56-16.18），无统计学差异；不同的溶栓药物之间无明显差别。尽管一些试验提示r-tPA出血风险较小，病人的获益较大。但目前尚无充足证据说明哪一种剂量、药物及给药方法更好一些，需要更大型的随机临床试验来证实。总之，溶栓治疗在有经验的研究中心并且严格选择病人使用时会得到有益的结果，但在常规临床实践中溶栓治疗不能被广泛的应用。

a) 关于心肌梗塞的治疗，许多大型临床随机试验都一致证明了溶栓可以降低病人的死亡率。一般在6个小时内进行治疗。r-tPA颅内出血的发生率较SK高，高龄（>65岁）、低体重(<70kg)、高血压(SBP≥170mmmHg，DBP≥95mmmHg)、应用t-PA是颅内出血的四个危险因素。当出血危险高的病人溶栓时，需要权衡利弊，为减少颅内出血，应使用SK。

目前的证据支持PTCA比溶栓治疗更有益，但目前最大最多中心参加的试验GUSTO2B试验得出的结论是：PTCA比溶栓治疗的优越性不明显。这一倾向提示，当采用最理想的溶栓治疗时，PTCA的优越性降低。相信随着医学的发展，更好的溶栓药物出现，PTCA的优越性将逐步降低。直接PTCA能直接判断冠脉通畅的级别，冠脉开通率更高，（一般能达到TIMI 3级），冠脉造影结果提示左主干闭塞者可立即转送做CABG，再闭塞率低，卒中危险性小，适用于老年、心源性休克等高危患者。在富有经验的医疗中心，能及时行PTCA时，直接PTCA可作为AMI再灌注的首选策略。绝大多数情况下，适宜的溶栓治疗仍将被认为是很好的再灌注策略。

八种血管紧张素转换酶抑制剂对高血压患者的临床疗效、安全性及成本效果的卫生技术评估

董碧蓉1 曹立亚2 周焱1徐英1兰奋2舒德芬1肖爱丽2常薪霞1杜坚宗1 王惠1李幼平3

（1四川大学华西医院老年科2中国药监局3中国循证医学中心）

摘要：目的：本研究从循证医学角度，对国内上市的8种血管紧张素转换酶抑制剂（AECIs），

针对膏血压病人，就其临床疗效、安全性、成本-效果、依从性和伦理等进行评价。方法：药物卫生技术评估方法，检索Medline, Cochrane图书馆, Embase和中国生物医学文献数据库等数据库，疗效分析纳入系统评价、随机临床对照试验，交叉试验等，安全性和药物经济学分析同时纳入观察性研究。按照国际评价标准对文献进行严格评价，纳入高质量研究。结果：八种AECIs的降压幅度与剂量呈正相关，任何一种AECI联合钙拮抗剂或利尿剂或b受体阻滞剂，降压效果更佳，新型AECIs降压作用强于依那普利和卡托普利。Meta分析显示，谷-峰比值小于50%的有培哚普利、贝那普利和卡托普利。八种ACEIs均有关于心脏保护的研究证据。慢性心衰：依那普利和卡托普利的高质量的研究证据最多；赖诺普利、培哚普利、西那普利和苯那普利仅观察了中间指标对心衰的影响。心脏保护药物间相互比较显示，福辛普利较卡托普利更安全，比依那普利效果好；赖诺普利优于卡托普利等均是以替代指标进行比较。心肌梗死：证据显示卡托普利、赖诺普利对急性期（心梗36小时内）可以降低病死率；依那普利、卡托普利、雷米普利和培哚普利对梗死后期（梗死后3天服用）明显降低总死亡率。仅雷米普利、赖诺普利和培哚普利有证据显示对脑血管具有保护作用。尚未发现有关苯拉普利对肾脏的保护性研究，其他ACEIs这方面的研究数量亦较少，显示一定程度减少蛋白尿和延缓肾衰的作用。新型ACEIs不良反应与卡托普利相似，但发生率略低。不良反应研究表明：雷米普利、培哚普利、贝那普利发生率少于卡托普利，福辛普利耐受性高于依那普利。有关ACEIs成本-效果研究的文献不多，有证据表明依那普利治疗心衰具有良好的成本-效果，而赖诺普利更好。雷米普利和卡托普利分别与钙拮抗剂或利尿剂联用，可降低治疗成本。缺乏ACEIs在伦理方面的研究证据。结论：现有研究证据不能对八种ACEIs进行简单的总排序，并非所有ACEIs在心、脑、肾器官保护方面都有充分证据，临床医生在面对八种ACEIs的选择时，首先应该选择在这一方面有足够研究证据的ACEI。

关键词：ACEIs 高血压卫生技术评估

Health Technology Assessment of Eight ACEIs for Hypertension

DONG Bi-rong1 CAO Li-ya2 ZHOU Yan1 XU Yin1 2 FEN LAN 2 SU De-fen1 XIAO Ai-li2 CHAN Xinxia1 DU Jan-zhong1 LI You-pin3

1 Department of Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China.

2 Center for Drug Re-evaluation, State Food and Drug Administration of China, Beijing 10038,China..

3 The Chinese Cochrane Center, West China Hospital, Sichan University, Chengdu, 610041, China.

【ABSTRACT】Objectives To evaluate the clinical effectiveness, safety, cost-effecitiveness of eight angiotensin converting enzyme inhibitors(AECIs)in order to provide evidences for adjustment of essential medicines lists in China and choice of clinician. Method Collecting all the clinical trial by searching Medline, Cochrane Library, Embase and Chinese Biomedical Database and doing critical appraise, high quality randomized controled trials and systematic reviews were included to assess the effectiveness of ACEIs, Non-randomized controlled trials also be included to evaluate the safe and cost-effectiveness . Results There is better effect of antihypertension and endurance in new ACEIs than enalapril and captopril, Meta-analysis showed that T/P ratio less than 50% are prindopril, benazepril and captopril in eight ACEIs. Enalapril and captopril have the most evidences of heart protection in chronic heart failure. The lisinopril, Prindopril,benazepril and cilazapril positive influence on heart failure only showed in surrogates. In AMI, there are evidences suggesting that captopril, lisinopril can reduce the total death rate of acute period(during 36hrs of AMI). Enalapril,captopril, ramipril and prindopril has the heart protection in late period of AMI(3days after AMI). Only ramipril, lisinopril and prindopril have the evidences to support the protective effect to cerebral vessels. Although not more evidences, all the ACEIs

except benzepril shows that can diminish proteinuria and delay the renal failure. The new types of ACEIs have the similar adverse reaction to enalapril and captopril, while incidence is lower than enalapril and captoril. Few evidences on cost-effectiveness of ACEIs, there are evidences to show enalapril has good cost-effecitiveness in treating heart failure, while lisinopril better than enalapri. The studies on ethics were not identified. Conclusi ons It’s difficult to generally rank the eight ACEIs according to acquired evidences. Each of eight AEICs has the different evidence in different organ protection. It suggests that clinicians should choose ACEI which has enough evidences to treat patients during considering different the conditions of the patients and also considering applicability,cost-effectiveness and adverse reactions of various ACEIs.

Key words: assessment ACEIs hypertension